Recent studies have demonstrated that hypertension correlates with tumorigenesis and prognosis of clear cell renal cell carcinoma (ccRCC); however, the underlying molecular mechanisms remain unclear. By analyzing bulk and scRNA-seq data and experimental examining of surgical excised ccRCC samples, we found that TIMP3, a pivotal paracrine factor in suppressing tumor progression, was significantly reduced in the tumor endothelial cells of hypertensive ccRCC patients. Besides, in tumor xenograft of NCG mouse model, compared with saline normotensive group the expression of TIMP3 was significantly decreased in the Ang II-induced hypertension group. Treating human umbilical vein endothelial cells (HUVECs) with the plasma of hypertensive ccRCC patients and miR-21-5p, elevated in the plasma of hypertensive ccRCC patients, reduced the expression of TIMP3 compared with normotensive and control littermates. We also found that the inhibition of TIMP3 expression by miR-21-5p was not through directly targeting at 3’UTR of TIMP3 but through suppressing the expression of TGFBR2. In addition, the knockout of TGFBR2 reduced TIMP3 expression in HUVECs through P38/ EGR1 (early growth response protein 1) signaling axis. Moreover, via co-culture of ccRCC cell lines with HUVECs and mouse tumor xenograft model, we discovered that the TIMP3 could suppress the proliferation and migration of ccRCC. Implications: Overall, our findings shed new light on the role of hypertension in promoting the progression of ccRCC and provide a potential therapeutic target for ccRCC patients with hypertension.